Is CCDC3 p.Met185Thr (c.554T>C) pathogenic?

CCDC3 p.Met185Thr (c.554T>C) is classified Uncertain significance in CCDC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-06). AlphaMissense: likely pathogenic (0.5866); Very rare (popmax 0.00934%, afr).

How common is CCDC3 p.Met185Thr (c.554T>C) in the general population?

CCDC3 p.Met185Thr (c.554T>C) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about CCDC3 p.Met185Thr (c.554T>C)?

AlphaMissense predicts likely pathogenic (score 0.5866) — an in-silico prediction, not a clinical call.

CCDC3 p.Met185Thr

c.554T>C · VCV4649472

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5866 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5866	likely pathogenic
REVEL	0.162	moderately benign-leaning
SaProt	LLR -4.80	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.55 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 103 kb · p 0.00074 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00934% African / African-American · 7/74,916 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000434% 7/1,613,910 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CCDC3
Protein: p.Met185Thr
Coding: c.554T>C
MANE Select: NM_031455
Type: single nucleotide variant
Location: chr10:12898675 (GRCh38)
Gene constraint: LOEUF 1.79 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13

Full CCDC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC3 p.Ala19Val Uncertain significance ★ ⚠ same type
CCDC3 p.Ala21Ser Uncertain significance ★ ⚠ same type
CCDC3 p.Ala21Thr Uncertain significance ★ ⚠ same type
CCDC3 p.Ala250Val Uncertain significance ★ ⚠ same type
CCDC3 p.Ala253Thr Uncertain significance ★ ⚠ same type
CCDC3 p.Arg20Cys Uncertain significance ★ ⚠ same type
CCDC3 p.Arg213Cys Uncertain significance ★ ⚠ same type
CCDC3 p.Arg215Trp Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ccdc3-p-met185thr (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown